Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety and for all purposes.
Bendamustine (BDM) represents one of the earliest rationally designed anticancer drugs that incorporated three functional groups, a benzimidazole ring, a mechlorethamine group and a butanoic acid residue. These groups putatively endowed BDM with both alkylator and antimetabolite activities. BDM has been found to be especially effective in hematologic-related cancers including chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) for which the FDA has approved its use, and multiple myeloma. The differences in the expression pattern of genes involved in DNA-damage stress response, apoptosis, cell cycle, mitosis and DNA replication after treatment with BDM and standard alkylating agents suggested that BDM elicits a different cytotoxic response mediated by a mechanism of action that differs from other alkylating agents.
The deoxycytidine analogue gemcitabine (2′,2′-difluorodeoxycytidine, a.k.a. Gem) is an antimetabolite used for the treatment of advanced pancreatic, lung, bladder and breast cancer. In particular, Gem is the drug of choice for metastatic pancreatic cancer, but it only exhibits a modest increase (months) in overall survival and amelioration of symptoms in comparison to 5-fluorouracil. Gem is an ideal candidate for combination chemotherapy due to the lack of cross-resistance with other agents. On the other hand, inter-patient variability of anti-tumor activity and toxicity, and ultimately development of resistance, underscore the need to improve Gem efficacy.